Atherosclerosis is a leading cause of major vascular events, myocardial infarction, and ischemic stroke. Tryptophan (TRP) catabolism was recognized as an important player in inflammation and immune response having together with oxidative stress (OS) significant effects on each phase of atherosclerosis. The aim of the study is to analyze the relationship of plasma levels of TRP metabolites, inflammation, and OS in patients with neurovascular diseases (acute ischemic stroke (AIS), significant carotid artery stenosis (SCAS)) and in healthy controls. Blood samples were collected from 43 patients (25 with SCAS, 18 with AIS) and from 25 healthy controls. The concentrations of twelve TRP metabolites, riboflavin, neopterin (NEO, marker of inflammation), and malondialdehyde (MDA, marker of OS) were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Concentrations of seven TRP metabolites (TRP, kynurenine (KYN), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), anthranilic acid (AA), melatonin (MEL), tryptamine (TA)), NEO, and MDA were significantly different in the studied groups. Significantly lower concentrations of TRP, KYN, 3-HAA, MEL, TA, and higher MDA concentrations were found in AIS compared to SCAS patients. MDA concentration was higher in both AIS and SCAS group (p < 0.001, p = 0.004, respectively) compared to controls, NEO concentration was enhanced (p < 0.003) in AIS. MDA did not directly correlate with TRP metabolites in the study groups, except for 1) a negative correlation with kynurenine acid and 2) the activity of kynurenine aminotransferase in AIS patients (r = −0.552, p = 0.018; r = −0.504, p = 0.033, respectively). In summary, TRP metabolism is clearly more deregulated in AIS compared to SCAS patients; the effect of TRP metabolites on OS should be further elucidated.

Background: Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes. Aim: It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment. Methods: In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy. Results: Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p < 0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B < CYP2C9 *1/*1 + VKORC1 A/B < CYP2C9 *1/*2 + VKORC1 B/B. Conclusion: Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.

Alterations in lipid metabolism mediated by oxidative stress play a key role in the process of atherosclerosis and superimposed thrombosis; these can lead to acute coronary syndrome (ACS) and acute ischemic stroke (AIS). Multiple studies have shown that the formation of atheromatous lesions is initiated by oxidation of low-density lipoproteins incorporated into the intima of the vessel wall. Here, we studied lipids in plasma samples from three cohorts: 61 patients with ACS (group A), 49 patients with AIS (group D), and 82 controls (group K). Untargeted lipidomics based on high-performance liquid chromatography coupled to mass spectrometry (UHPLC-HRMS) was employed to obtain comprehensive information on whether relationships exist between these patient categories based on lipid patterns. In addition, malondialdehyde (MDA) as a standard marker of oxidative stress was monitored. The most characteristic lipids in group K were fatty acyls of hydroxyfatty acids (FAHFAs). As expected, MDA concentrations were the lowest in group K. Our findings can better explain ongoing pathologies, both acute and chronic, with the potential for future diagnosis and treatment.

Background: Variable response after clopidogrel is well documented and may affect major adverse clinical events after stroke. Impact of CYP2C19 genetic polymorphisms is an established marker linked to variable response after clopidogrel. However, the association of certain genetic polymorphisms with prediction of major adverse clinical events following stroke still remains controversial, especially in Caucasians. Study Question: The primary aim was to evaluate the impact of CYP2C19 allele *2 in heterozygote form on major adverse clinical events in Caucasian poststroke survivors treated with clopidogrel. The secondary aim was to analyze the potential link between CYP2C19 genetic polymorphism and variable response after clopidogrel. Study Design: One hundred thirty patients of Caucasian origin following documented ischemic stroke were included. Platelet reactivity was assessed by light transmittance aggregometry (LTA) and matched with various CYP2C19 loss-of-function genetic polymorphisms and major adverse clinical events (composite of vascular deaths, stroke/transient ischemic attack, and myocardial infarction). Results: Over the mean follow-up of 14.9 months, 19 patients experienced major adverse clinical events. The risk of major adverse clinical events was nearly 3-fold in loss-of-function allele carriers (hazard ratio = 2.904; 95% confidence interval, 1.083–7.786; P = 0.013), whereas the risk of ischemic stroke or transient ischemic attack alone was also higher (hazard ratio = 3.170; 95% confidence interval, 1.281–7.849; P = 0.034). Platelet activity was strongly associated with allele *2 status (r_s = 0.21, P = 0.016) but not with other genetic polymorphisms. Carriers of allele*2 exhibited lower platelet response to adenosine diphosphate—mean LTA (30.1% vs. 42.0%; P = 0.017). There were no significant differences in LTA results with other agonists. Strong association of increase in adenosine diphosphate–induced aggregation with diabetes mellitus (r_s = 0.20, P = 0.023), increasing age (r_s = 0.23, P = 0.008), and conversely diminishing over increased weight (r_s = 0.23, P = 0.009) was also detected. The carriers of other gene allele variants lack uniformed impact on variable response after clopidogrel. Conclusions: Even heterozygous CYP2C19*2 allele carriers among Caucasian patients after ischemic stroke had a higher risk of major adverse clinical events. The LTA, however, did not predict major adverse clinical events. The exact clinical utility of these findings is still uncertain and requires large outcome-driven randomized trial in Caucasians for proof of concept.